title: A proangiogenic signature is revealed in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma.
abstract: Resistance to antiangiogenic therapies is a critical problem that has limited the utility of antiangiogenic agents in clinical settings. However, the molecular mechanisms underlying this resistance have yet to be fully elucidated. In this study, we established a novel xenograft model of acquired resistance to bevacizumab. To identify molecular changes initiated by the tumor cells, we performed human-specific microarray analysis on bevacizumab-sensitive and -resistant tumors. Efficiency analysis identified 150 genes upregulated and 31 genes downregulated in the resistant tumors. Among angiogenesis-related genes, we found upregulation of fibroblast growth factor-2 (FGF2) and fibroblast growth factor receptor-3 (FGFR3) in the resistant tumors. Inhibition of the FGFR in the resistant tumors led to the restoration of sensitivity to bevacizumab. Furthermore, increased FGF2 production in the resistant cells was found to be mediated by overexpression of upstream genes phospholipase C (PLCg2), frizzled receptor-4 (FZD4), chemokine [C-X3-C motif] (CX3CL1), and chemokine [C-C motif] ligand 5 (CCL5) via extracellular signal-regulated kinase (ERK). In summary, our work has identified an upregulation of a proangiogenic signature in bevacizumab-refractory HNSCC tumors that converges on ERK signaling to upregulate FGF2, which then mediates evasion of anti-VEGF therapy. These findings provide a new strategy on how to enhance the therapeutic efficacy of antiangiogenic therapy.
  
  
  CONCLUSIONS
  Novel xenograft model leads to the discovery of FGF as a promising therapeutic target in overcoming the resistance of antiangiogenic therapy in HNSCC.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Suite 500, Pittsburgh, PA 15213. kimsw2@upmc.edu.
authors.forename: Rekha
authors.initials: R
authors.lastname: Gyanchandani
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Ortega Alves
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Seungwon
authors.initials: S
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000068258:Bevacizumab; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C115711:PD 173074; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016222:Fibroblast Growth Factor 2; D000068258:Bevacizumab